1,3 imidazolidine derivatives and their use in the production of carbapenem

ABSTRACT

Preparation of new heterocyclic compounds characterized by 1,3-imidazolidine structure useful for stereoselective synthesis of optically pure key intermediates in 1β-methylcarbapenem production.

The present invention relates to 1,3 imidazolidine intermediates usefulin the stereoselective synthesis of carbapenem, in particular of1β-methylcarbapenem.

The heterocyclic compounds of this invention are represented in formula(I),

in which X is a halogen chosen from chlorine, bromine and iodine, Y ischosen from the group consisting of oxygen, sulphur and NR₅, where R₅ is(C₁-C₉)aliphatic, (C₃-C₈)alicyclic, (C₃-C₉)heterocyclic, phenyl, aryl orheteroaryl carrying up to three substituents chosen from halogen, nitrogroup, (C₁-C₃)alkoxy, E is chosen from the group consisting of oxygenand sulphur, R is is chosen from the group consisting of hydrogen,methyl, ethyl, propyl, isopropyl, (C₄-C₉)aliphatic alkyl,(C₃-C₉)alicyclic alkyl, 1-haloethyl(—CHX—CH₃) only when E is oxygen,aryl, heteroaryl, aryl(C₁-C₃)alkyl, heteroaryl(C₁-C₃)alkyl,(C₁-C₉)aliphatic alkyloxy, (C₃-C₉)alicyclic alkyloxy, aryloxy,heteroaryloxy, aryl(C₁-C₃)alkyloxy, heteroaryloxy,heteroaryl(C₁-C₃)alkyloxy, (C₁-C₉)aliphatic alkylthio, (C₃-C₉)alicyclicalkylthio, arylthio, heteroarylthio, aryl(C₁-C₃)alkylthio,heteroarylthio, heteroaryl(C₁-C₃)alkylthio, while R₁, R₂, R₃ and R₄ areindependently chosen from the group consisting of hydrogen, methyl,ethyl, (C₃-C₉)aliphatic alkyl, (C₃-C₉)alicyclic alkyl, heteroaryl,heteroaryl(C₁-C₃)alkyl, aryl, aryl(C₁-C₃)alkyl, possibly mutuallycombined to form an o-phenylene structure with the 1,3 imidazolidinering, such as a benzo[d]-2,3-dihydro-1H-imidazole structure, and, whenR₁ is coupled to R₂ and R₃ is coupled to R₄, they mutually combine toform an alkylene group or a cyclic spiro structure, such as ligands ofheterocyclo 1,3-imidazolidine.

As they are derived from a 2-halopropionic acid (CH₃—CHX—COOH in which Xhas the aforedefined meaning), the compounds of formula (I) are used forthe stereoselective synthesis of the advanced intermediate of formula(II),

a key chiral intermediate for the synthesis of various1β-methylcarbapenems, where G is chosen from the group consisting ofhydrogen and hydroxyl protective groups [from those described in varioustexts, such as “Protective Groups in Organic Synthesis” (1981)(published by John Wiley & Sons, New York, U.S.A.), “New ExperimentalChemistry” (Shin-Jikken Kagaku Koza” in Japanese) Vol. 14 (1978)(published by Maruzen, Tokyo, Japan), “Chimica Organica Applicata”(author Umberto Valcavi), published by CLUED, Milan, Italy, ISBN88-7059-041-0) and in the references mentioned in these three texts],i.e. (C₁-C₄)alkyl, methoxymethyl, methylthiomethyl, allyl, propargyl,methoxyethoxymethyl, (C₁-C₉)dialkylboryl, 9-borabicyclonon-9-yl,2,2,2-trichloroethoxymethyl, tetrahydropyranyl, substituted ethylschosen from 1-ethoxyethyl, 1-methyl-1-methoxyethyl, trichloroethyl,hence methyls substituted with aryls chosen from phenylmethyl,diphenylmethyl, triphenylmethyl, p-methoxyphenylmethyl,o-nitrophenylmethyl, p-nitrophenylmethyl, p-chlorophenylmethyl,diphenylmethyl, triphenylmethyl, and in addition substituted silylschosen from the trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, ort-butyldiphenylsilyl group, and moreover formyloyl, (C₁-C₅)alkanoyl,halogenated (C₁-C₃)alkanoyl, aryloyl chosen from benzoyl,p-methylbenzoyl, naphthoyl, and in addition (C₁-C₄)alkoxycarbonyl[preferably chosen from methoxycarbonyl, ethoxycarbonyl,isobutoxycarbonyl], halogenated ethoxycarbonyl [preferably chosen from2-iodo-ethoxycarbonyl and 2,2,2-trichloroethoxycarbonyl],(C₃-C₅)alkenylcarbonyl [preferably chosen from allyloxycarbonyl,3-methylallyloxycarbonyl], and arylmethoxycarbonyl [preferably chosenfrom phenyl methoxycarbonyl, p-methoxyphenylmethoxycarbonyl,2,4-dimethoxyphenyl methoxycarbonyl, o-nitrophenylmethoxycarbonyl,p-nitrophenylmethoxycarbonyl].

The compounds of formula (II) are known key chiral intermediates in thesynthesis of 1β-methylcarbapenem with antimicrobic activity.

The compounds of formula (II) are known to have been synthesized byvarious strategies, in particular as described and claimed inEP232786B1, by derivatives of a 2-halopropionic acid bindingheterocycles different from those described in the present invention.

Likewise to that described in EP232786B1, the compounds of formula (I)also react as enolates of a 2-halopropionic acid derivative withazetidinone intermediates of formula (III),

where G has the meaning described for the compounds of formula (II)while L is a nucleofugal ligand chosen from the group consisting ofhalogen, formyloyloxy, acetoxy, (C₂-C₅)alkylcarbonyloxy,(C₃-C₉)cycloalkylcarbonyloxy, (C₁-C₅)acyloxy chosen from unsaturatedsand halogenates in a position vicinal to the carbonyl, arylcarbonyloxy[preferably chosen from benzoyloxy, p-methylbenzoyloxy,p-methoxybenzoyloxy, p-chlorobenzoyloxy, p-nitrobenzoyloxy],(C₁-C₇)alkylsulphonyloxy, arylsulphonyloxy [preferably chosen fromphenylsulphonyloxy, p-chlorophenylsulphonyloxy,p-methylphenylsulphonyloxy], (C₁-C₇)alkylsulphonyl, arylsulphonyl[preferably chosen from phenylsulphonyl, p-chlorophenylsulphonyl,p-methylsulphonyl], (C₁-C₇)alkylsulphinyl, arylsulphinyl [preferablychosen from phenylsulphinyl, p-chlorophenylsulphinyl,p-methylphenylsulphinyl], and finally (C₁-C₇)alkylsulphenyl andarylsulphenyl [preferably chosen from phenylsulphenyl andp-chlorophenylsulphenyl]: the nature of the nucleofuge L is functionalon the condensation between the species (I), activated as enolate, andthe species (III), to obtain the new intermediate species (IIIb),

where G, Y, E, R₁, R₂, R₃ and R₄ have the meanings described for thecompounds (I) and (II), while R′ is chosen from the group consisting ofhydrogen, methyl, ethyl, propyl, isopropyl, (C₄-C₉)aliphatic alkyl,(C₃-C₉)alicyclic alkyl, heteroaryl, aryl(C₁-C₃)alkyl,heteroaryl(C₁-C₃)alkyl, (C₁-C₉)aliphatic alkyloxy, (C₃-C₉)alicyclicalkyloxy, aryloxy, heteroaryloxy, aryl(C₁-C₃)alkyloxy, heteroaryloxy,heteroaryl(C₁-C₃)alkyloxy, (C₁-C₉)aliphatic alkylthio, (C₃-C₉)alicyclicalkylthio, arylthio, heteroarylthio, aryl(C₁-C₃)alkylthio,heteroarylthio, heteroaryl(C₁-C₃)alkylthio.

The present inventors have surprisingly verified that the intermediatespecies (IIIb) is isolated stereoisomerically pure, i.e. the formaladdition of the species (I)-derived enolate to the species (III) hasproduced the species (IIIb) by stereospecific and stereoselectivereactivity.

The species (IIIb) presents four contiguous stereocentres identifiableby the common graphic ligand describers used in the relative structuralformulas, each characterized by a graphically explicit unequivocalabsolute configuration. The formal stereospecific addition comprises theinitial elimination of the nucleofugal species L, as HL, from theazetidinone species (III), by the formation of the correspondingtransient azetinone intermediate (IIIc),

on which the enolate deriving from the species (I) is stereospecificallyadded by the mechanism described in the review of Andrew H. Berks“Preparation of Two Pivotal Intermediates for the Synthesis of 1β-MethylCarbapenem Antibiotics”, Tetrahedron, (1996) 52(2) pages 331-375: hencefrom that stated, the formation of the species (IIIb) resulting from theaddition of the species (I)-derived enolate to the species (III), withelimination of the species HL, takes place by an elimination-additionmechanism.

The present inventors have also surprisingly verified that the compounds(Ib), included in the compounds of formula (I),

where E is equal to oxygen and R is equal to 1-haloethyl, have thepeculiar structural characteristic of comprising two equal ligands, eachof which is able to locate a carbanion of enolate type on the carbonvicinal to the carbonyl.

The species (Ib) is therefore a heterocyclic structure able to generatetwo carbanions, hence behaving as a bidentate reagent; in particular,this is characteristic has proved surprisingly advantageous when it hasbeen found that the first carbanion formed on one of the ligandsoperates as base on the species (III) to form the reactive intermediate(IIIc), then subsequently the second carbanion formed on the otherligand is able to add as nucleophile to the just formed species (IIIc),to obtain the species (IIId),

included in the products of formula (IIIb).

Consequently, to obtain the stereoisomerically pure species (IIId), thecompounds (Ib) are advantageously usable in molar quantities less eventhan 50% compared with other heterocyclic derivatives of a2-halopropionic acid known up to the present time in the state of theart, precisely because they display double enolate characteristics, i.e.bifunctional or “bidentate”, as schematized below,

able to act both as a base on the amide nitrogen of the species (III)and as a nucleophile on the transient reactive intermediate (IIIc) thusformed, in accordance with the following scheme.

is Any other monofunctional enolate (“monodentate”), such as all thoseknown up to the present time in the state of the art, is used in largeexcess because it has initially to act as a base to obtain the species(IIIc), then as a nucleophile to obtain the addition product; in thisrespect, as is apparent from the experimental examples of EP232786B1,the highest yields are achieved using at least two molar equivalents ofthe chosen heterocyclic derivative of 2-halopropionic acid with respectto the reacting species (III).

The species (IIIb) is then transformed directly into the species (II) bytreatment with hydrogen peroxide in the presence of an alkali metalhydroxide and with the final addition of a reducing species, preferablysodium sulphite.

As an alternative to the above direct transformation, the species (IIIb)can be transformed into the species (IIIe),

where G has the meaning defined for the compounds of formula (IIIb),while E₁ is chosen from the group consisting of (C₁-C₄)alkyl, allyl,arylmethyl, diarylmethyl, triarylmethyl, in which each aryl substituentcan optionally present, as aromatic ring ligands, up to threesubstituents independently chosen from the group consisting of nitro,(C₁-C₄)alkyl, (C₁-C₄)alkoxy, fluorine, chlorine, bromine and iodine.

Hence, the compounds of formula (II) are obtained from the species(Ille) by the procedure described in EP232786B1, or by other knownmethods for deprotecting esters, by means for example of the use ofpalladium complexes in the case in which E₁ is an allyl group.

The species (II) is obtained stereoisomerically pure both from compoundsof formula (IIIb) and from derivatives of formula (IIIe).

The compounds of formula (I) are synthesized starting from the compounds(IV),

where Y, R₁, R₂, R₃ and R₄ have the meaning described for the compoundsof formula (I), prepared as described in U.S. Pat. No. 4,681,948,EP232786B1 and EP573667B1 and, for a general approach to the synthesisof 2-imino-1,3-imidazolidine heterocycles, in “Best Practice & ResearchClinical Anaesthesiology”, 14(2), 237-246 (2000), also considering thereferences mentioned in said four documents.

Firstly, a compound included in those described in formula (IV) isreacted in the presence of a base chosen from alkali metal hydrides,(C₁-C₄)alkyllithium derivatives, aryllithium derivatives,heteroaryllithium derivatives and alkali metals with up to one or lessthan one molar equivalent of an activated derivative of formula (V),

where E and R have the meaning described for the compounds of formula(I), while Y₁ is a nucleofugal group typical of acylation reactions[preferably chosen from the group consisting of chlorine, bromine andiodine, independently of X], in at least one aprotic inert solvent,preferably chosen from tetrahydrofuran, dioxane, 1,2-dimethoxyethane, C₆alicyclic hydrocarbons, (C₆-C₁₀)aliphatic hydrocarbons, benzene,(C₁-C₃)alkylsubstituted benzene, (C₁-C₃)dialkylsubstituted benzene,(C₁-C₃) trialkylsubstituted benzene, halogenated (C₁-C₃)aliphatichydrocarbons, glyme, diglyme, di(C₁-C₄)alkylethers,N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone andhexamethylphosphoramide, at temperatures between −80° C. and +50° C., toobtain the intermediate (IVbis)

which, even non-isolated, is made to react with a further equivalent ofa base chosen from those mentioned in at least one aprotic inertsolvent, possibly in mixture with other solvents of the same type, thenadding at least one molar equivalent of 2-halopropionyl derivative (VI)

where X has the same meaning as for the compounds of formula (I) and Y₂is a nucleofugal group typical of acylation reactions [preferably chosenfrom the group consisting of chlorine, bromine and iodine, independentlyof X], at temperatures between −80° C. and +50° C., to isolate thecompound (I).

If the compound (Ib) is synthesized, i.e. when the reagent (V) coincideswith the reagent (VI), the corresponding diastereoisomers (Ic), (Id),(Ie) and (If)

can be obtained.

If R₁, R₂, R₃ and R₄ are in the form of identical pairs, with R₂ equalto R₃ and R₁ equal to R₄, and the equal substituents of said pairs aremutually correlatable by trans stereochemistry, (Ic) and (Ie) arediastereoisomers while (Id) and (If) coincide, whereas when the equalsubstituents of said pairs are mutually correlatable by cisstereochemistry, (Ic) and (Ie) are enantiomers, hence isolated togetheras racemate, while (Id) and (If) are diastereoisomers, whereas incontrast, if R₁, R₂, R₃ and R₄ are identical, (Ic) and (Ie) areenantiomers and are isolated together as racemate, while (Id) and (If)coincide in a single mesoform.

Subsequently, the compounds of formula (I) react with the compounds(III) to obtain the intermediates (IIIb) as pure stereoisomer, inaccordance with Reformatsky-type reactivity, in the presence of powderedzinc or other reducers described in the report Tetrahedron 60 (2004),9325-9374 (report 692).

It has also been verified that the reaction of adding the appropriatespecies (Ib) to the species (IIIc) deriving from the species (III)enables the intermediate species (IIId) to be obtained, with G equal tot-butyldimethylsilyl, Y equal to oxygen, R₁=R₂=R₃=R₄=methyl, as purediastereoisomer with reproducible higher yields when, of the possiblechoices for the species (Ib), the racemate (Ic)+(Ie) is preferred to themesoform (Id); in addition the mesoform (Id) can itself beadvantageously transformed into the more efficient racemate (Ic)+(Ie) bycatalyzed acid rebalancing in solution in which the sp³ carbon atoms areinverted as stereocentres binding the group X so that theracemate/mesoform diastereoisomeric ratio, from the equilibriumviewpoint, is about 65/35, to hence display an overall enrichment in thesought racemate of the resultant solution which is then isolated insolid form by known chromatographic methods.

The compound (I) and the powdered zinc can be used in molar excess toincrease the condensation yield to obtain the intermediate (IIIb): thezinc is used in a quantity from 1 to 5 molar equivalents, preferablyfrom 2 to 5 molar equivalents, with respect to the substrate (III),while the compound (I) is used from 0.5 to 3 molar equivalents,preferably from 1 to 3 molar equivalents, with respect to the substrate(III). If the compound (I) used is the diastereoisomerically purecompound (Id), the reaction displays high yields of thestereoisomerically pure intermediate (IIId) even with 1 molar equivalentof zinc and 0.5 molar equivalents, with respect to the substrate (III),of (Id) which, in this case, is the limiting agent of the reaction. Thecondensation reaction between the compounds of formula (I) and (III),for formation of the intermediate (IIIb), is conducted at temperaturesbetween −50° C. and +150° C., preferably between 0° C. and 100° C.

The species (IIIb) is then directly transformed into the species (II) bytreatment with hydrogen peroxide, used from 1 to 20 molar equivalentswith respect to the substrate (IIIb), in the presence of an alkali metalhydroxide (preferably lithium hydroxide) used from 1 to 10 molarequivalents with respect to the substrate (IIIb), in aqueous organicsolvents chosen from dioxane, tetrahydrofuran, N,N-dimethylformamide,(C₁-C₄)aliphatic alcohols, N,N-dimethylacetamide and N-methylpyrrolidoneat a reaction temperature between −10° C. and +30° C., and adding areducing species, preferably sodium sulphite, on reaction termination.

Alternatively, the intermediate (IIIb) is added in a (C₁-C₄)aliphaticalcohol in the presence of an alkali metal carbonate or alcoholate ofthe (C₁-C₄)aliphatic alcohol chosen as solvent, or adding the species(IIIb) in an aprotic inert solvent chosen from (C₁-C₄)alkylethers,tetrahydrofuran, dioxane, 1,2-dimethoxyethane, glyme, diglyme,(C₆-C₁₀)aliphatic hydrocarbons, (C₇-C₉)alicyclic hydrocarbons,cyclohexane, cyclohexene, benzene, toluene, and other aromatichydrocarbons, polar aprotic solvents chosen from N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoramide, inthe presence of a (C₁-C₄)aliphatic alcoholate or an arylmethoxylate or adiarylmethoxylate or a triarylmethoxylate of an alkali metal, in whicheach aryl substituent can optionally present, as aromatic ligands, up tothree substituents independently chosen from the group consisting ofnitro, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, leaving the mixture to react forabout 1 hour at a temperature between −20° C. and +50° C. to obtain thespecies (IIIe), which is then transformed into the optically pure keyintermediate (II), as illustrated in EP232786B1.

Proposed non-limiting experimental examples of the invention aredescribed below.

EXAMPLES 1-a AND 1-b Preparation and Isolation of the Diastereoisomers(Ic) and (Id), with X=Bromine, Y=Oxygen, R₁=R₂=R₃=R₄=Methyl Example 1-a

200 mg of the compound (IV), with R₁=R₂=R₃=R₄=methyl and Y=oxygen aresuspended in 10 ml of anhydrous tetrahydrofuran in a 50 ml 4-neck flaskunder an inert argon atmosphere. The suspension is cooled for 5 minutesto 0° C. in an ice bath. 1.8 ml of 1.6M n-butyllithium in hexane areadded in two portions under strong agitation, the solution becomingclear after a few minutes. It is agitated for 10 minutes at 0° C. It isthen poured (under an inert argon atmosphere) through a narrow tubedropwise into a solution of 2-bromopropionyl bromide (317 μl; 3.0mmoles) in 5 ml of tetrahydrofuran under energetic agitation, maintainedat 0° C. in an ice bath. The addition lasts about 20 minutes. It is leftunder agitation at 0° C. for 10 minutes, and then at ambient temperaturefor 30 min.

The reaction is then quenched by adding 20 ml of phosphate buffer at pH6.5. The tetrahydrofuran is evaporated in a rotavapor. The aqueoussolution containing white crystals in suspension is extracted 3 timeswith ethyl acetate, and dried over sodium sulphate for 30 min at 0° C.It is filtered and evaporated to obtain 560 mg of crude residueconsisting of the diastereoisomers (Ic) and (Id).

The diastereoisomers obtained are separated by chromatography on asilica gel column, eluting with a 9/1 v/v cyclohexane/ethyl acetatesolution, to obtain 302 mg of compound (Ic) as racemate (Ic)+(Ie), and255 mg of compound (Id) as single mesoform.

¹HNMR-CDCl₃—300 MHz: (Ic)+(Ie) (racemate) 1.45 ppm (singlet, 12H), 1.85ppm (doublet, J=6.6 Hz, 6H), 5.84 ppm (quartet, 4H), (Id) 1.44 ppm(singlet, 6H), 1.46 ppm (singlet 6H), 1.84 ppm (doublet, J=6.6 Hz, 6H),5.75 ppm (quartet, 4H). The structure and the absolute configuration ofthe obtained compounds were defined by analyzing the values of thechemical shifts of the two products and by PM3 computational analysis.

Example 1-b

The reaction of example 1-a was repeated starting from 1.0 g of compound(IV), to obtain 2.8 mg of crude residue consisting of thediastereoisomers (Ic) and (Id). The diastereoisomers obtained areseparated by chromatography on an MPLC column, eluting with a 95/5 v/vcyclohexane/ethyl acetate solution, by means of a Biotage 50 g KP-SILSnap Flash cartridge column, flow 30 ml/min, to obtain 1.5 g of compound(Ic) as racemate (Ic)+(Ie) (product least retained in the column withRf=0.71), and 1.2 g of compound (Id) (product most retained in thecolumn with Rf=0.40), as single mesoform.

¹HNMR-CDCl₃—300 MHz: the ¹HNMR characterizations for compound (Ic)+(Ie)(racemate) and compound (Id) (mesoform) are superimposable on thosedescribed in example 1-a. The structure and the absolute configurationof the obtained compounds were confirmed by analyzing the values of thechemical shifts of the two products and by PM3 computational analysis.

EXAMPLE 2 Conversion of the Mesoform (Id) into the CorrespondingRacemate (Ic)+(Ie), with R₁=R₂=R₃=R₄=Methyl, Y=Oxygen and X=Bromine

200 mg of the product (Id) are fed into 50 ml of acetonitrile to which0.5 ml of 65% w/w aqueous hydrobromic acid are added and the mixtureagitated for about 4 hours until equilibrium is reached in which theracemate/mesoform ratio is about 65/35. The solution is evaporated in arotavapor to obtain 200 mg of a crude product consisting of 32.5% (Ic),32.5% (Ie) and 35% (Id), hence purifiable by chromatography, on thebasis of that indicated above for example 1-a and example 1-b, toisolate the raceme product (Ic)+(Ie) in pure form.

EXAMPLES 3-a, 3-b AND 3-c Preparation of the Intermediate (IIId), withY=Oxygen, G=T-Butyldimethylsilyl, R₁=R₂=R₃=R₄=Methyl Example 3-a

431 mg of compound (III), with G=t-butyldimethylsilyl and L=acetoxy, aredissolved into 3 ml anhydrous tetrahydrofuran in the presence of 121.4mg of activated powdered zinc under an inert argon atmosphere. 6 ml of asolution in anhydrous tetrahydrofuran of 306 mg of compound (Ic) (asracemate) are added dropwise over a time of 50 minutes to thesuspension, agitated magnetically and heated under reflux by a bath at+90° C. The mixture is then heated under reflux for a further 30minutes. It is allowed to cool to ambient temperature under agitationfor 15 minutes. The mixture is then cooled to 0° C., then adding 20 mlof a phosphate buffer at pH 6.5, to precipitate a crystalline whitesolid. The tetrahydrofuran is removed from the mixture by evaporationunder reduced pressure. The aqueous solution obtained is extracted threetimes with ethyl acetate. The organic phase is washed once with waterand dried with sodium sulphate for 12 hours at −10° C. The crudereaction product is purified by chromatography on a silica gel column,eluting with a cyclohexane/ethyl acetate solution at a gradient startingfrom 9/1 v/v cyclohexane/ethyl acetate, until the cyclohexane/ethylacetate ratio=7/3 v/v.: 13 mg of product (IIId) are obtained.

¹HNMR-CDCl₃—300 MHz: (IIId) 0.09 ppm (singlet, 6H), 0.89 ppm (singlet,9H), 1.13-1.24 ppm (9H), 1.39-1.44 ppm (12H), 2.87 ppm (multiplet, 1H),2.94 ppm (multiplet, 1H), 3.06 (multiplet, 1H), 3.96 ppm (multiplet,1H), 4.12 ppm (multiplet, 1H), 4.22 ppm (multiplet, 1H), 5.91 (singlet,1H).

Example 3-b

582 mg of compound (III), with G=t-butyldimethylsilyl and L=acetoxy, aredissolved in 3 ml anhydrous tetrahydrofuran in the presence of 219 mg ofactivated powdered zinc under an inert argon atmosphere. 14 ml of asolution of 700 mg of compound (Ic) (as racemate) are added dropwiseover a time of 50 minutes to the suspension, agitated magnetically andheated under reflux by a bath at +90° C. The mixture is then heatedunder reflux for a further 30 minutes. It is allowed to cool to ambienttemperature under agitation for 15 minutes. The mixture is then cooledto 0° C., then adding 40 ml of a phosphate buffer at pH 6.5, toprecipitate a crystalline white solid. The tetrahydrofuran is removedfrom the mixture by evaporation under reduced pressure. The aqueoussolution obtained is extracted three times with ethyl acetate. Theorganic phase is washed once with water and dried with sodium sulphatefor 12 hours at −10° C.

The dried solution is then evaporated and the crude reaction product ispurified by chromatography on an MPLC column with silica gel (column:Biotage 50 g KP-SIL Snap Flash cartridge, flow 30 ml/min) eluting withan 8/2 v/v cyclohexane/ethyl acetate solution, 746 mg of product (IIId)are obtained.

¹HNMR-CDCl₃—300 MHz: the ¹HNMR characterization for compound (IIId) issuperimposable on that described in example 2-a.

Example 3-c

The procedure of example 3-a is followed but using 102 mg of compound(III), with G=t-butyldimethylsilyl and L=acetoxy, in the presence of 29mg of activated powdered zinc and 73 mg of compound (Id) (mesoform)instead of (Ic).

After chromatographic purification as described in example 2, 70 mg ofproduct (IIId) are obtained.

¹HNMR-CDCl₃—300 MHz: the ¹HNMR characterization for compound (IIId) issuperimposable on that described in example 2-a.

EXAMPLE 4 Preparation of the Compound of Formula (II), withG=T-Butyldimethylsilyl

355 mg of 37% hydrogen peroxide (3.12 mmol) followed by 71 mg of lithiumis hydroxide monohydrate (1.8 mmol) are added under agitation to a 0.05Msolution consisting of 300 mg (0.65 mmol) of compound (111b), withG=t-butyldimethylsilyl, Y and E both equal to oxygen, R′=ethyl,R₁=R₂=R₃=R₄=methyl, dissolved in a solution consisting oftetrahydrofuran/water=3/1 v/v cooled to 0° C. The mixture is agitatedfor 1 hour at 0° C., monitoring the disappearance of the substrate(IIIb) by TLC (eluent cyclohexane/ethyl acetate=8/2 v/v). At the end ofthe reaction sufficient sodium sulphite is added to eliminate theperoxides, as evaluated by starch-iodine paper. The tetrahydrofuran isthen evaporated in a rotavapor and the aqueous phase acidified with 10%w/w aqueous hydrochloric acid until a white precipitate appears which isextracted with three 10 ml portions of ethyl acetate. The organicsolution obtained is dried over sodium sulphate and evaporated in arotavapor to obtain 190 mg of the compound of formula (II) in solidform.

1. A heterocyclic compound of formula (I):

wherein: X is a halogen selected from the group consisting of chlorine,bromine and iodine; Y is selected from the group consisting of oxygen,sulphur and NR₅; R₅ is (C₁-C₉)aliphatic, (C₃-C₉)alicyclic,(C₃-C₉)heterocyclic, phenyl, aryl, or heteroaryl carrying up to threesubstituents selected from the group consisting of halogen, nitro group,and (C₁-C₃)alkoxy; E is selected from the group consisting of oxygen andsulphur; R is selected from the group consisting of hydrogen, methyl,ethyl, propyl, isopropyl, (C₄-C₉)aliphatic alkyl, (C₃-C₉)alicyclicalkyl, and 1-haloethyl(—CHX—CH₃) only when E is oxygen, aryl,heteroaryl, aryl(C₁-C₃)alkyl, heteroaryl(C₁-C₃)alkyl, (C₁-C₉)aliphaticalkyloxy, (C₃-C₉)alicyclic alkyloxy, aryloxy, heteroaryloxy,aryl(C₁-C₃)alkyloxy, heteroaryl(C₁-C₃)alkyloxy, (C₁-C₉)aliphaticalkylthio, (C₃-C₉)alicyclic alkylthio, arylthio, heteroarylthio,aryl(C₁-C₃)alkylthio, and heteroaryl(C₁-C₃)alkylthio; R₁, R₂, R₃ and R₄are independently selected from the group consisting of hydrogen,methyl, ethyl, (C₃-C₉)aliphatic alkyl, (C₃-C₉)alicyclic alkyl,heteroaryl, heteroaryl(C₁-C₃)alkyl, aryl, and aryl(C₁-C₃)alkyl,optionally mutually combined to form an o-phenylene structure with the1,3 imidazolidine ring, such as a benzo[d]-2,3-dihydro-1H-imidazolestructure, and, such that when R₁ is coupled to R₂ and R₃ is coupled toR₄, they mutually combine to form an alkylene group or a cyclic spirostructure, such as ligands of heterocyclo 1,3-imidazolidine.
 2. Thecompound of claim 1, wherein Y and E are independently selected from thegroup consisting of oxygen and sulphur.
 3. The compound of claim 1,wherein E is oxygen and R is 1-haloethyl(—CHX—CH₃).
 4. The compound ofas claimed in claim 1, wherein: E represents oxygen; and R is1-haloethyl(—CHX—CH₃), such that the absolute configuration of each ofthe two stereocentres binding a substituent X is graphically schematizedin the following formulas (Ic), (Id), (Ie) and (If):


5. A heterocyclic compound of formula (IIIb):

wherein: Y is selected from the group consisting of oxygen, sulphur andNR₅; E is selected from the group consisting of oxygen and sulphur; R₁,R₂, R₃ and R₄ are independently selected from the group consisting ofhydrogen, methyl, ethyl, (C₃-C₉)aliphatic alkyl, (C₃-C₉)alicyclic alkyl,heteroaryl, heteroaryl(C₁-C₃)alkyl, aryl, and aryl(C₁-C₃)alkyl,optionally mutually combined to form an o-phenylene structure with the1,3 imidazolidine ring, such as a benzo[d]-2,3-dihydro-1H-imidazolestructure, and, such that when R₁ is coupled to R₂ and R₃ is coupled toR₄, they mutually combine to form an alkylene group or a cyclic spirostructure, such as ligands of heterocyclo 1,3-imidazolidine; G isselected from the group consisting of hydrogen, (C₁-C₄)alkyl,methoxymethyl, methylthiomethyl, allyl, propargyl, methoxyethoxymethyl,(C₁-C₉)dialkylboryl, 9-borabicyclonon-9-yl, 2,2,2-trichloroethoxymethyl,tetrahydropyranyl, a substituted ethyl group selected from the groupconsisting of 1-ethoxyethyl, 1-methyl-1-methoxyethyl, andtrichloroethyl, an aryl-substituted methyl group selected from the groupconsisting of phenylmethyl, diphenylmethyl, triphenylmethyl,p-methoxyphenylmethyl, o-nitrophenylmethyl, p-nitrophenylmethyl, andp-chlorophenylmethyl, a substituted silyl group selected from the groupconsisting of trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, andt-butyldiphenylsilyl group, formyl, (C₁-C₅)alkanoyl, halogenated(C₁-C₃)alkanoyl, an aryloyl selected from the group consisting ofbenzoyl, p-methylbenzoyl, and naphthoyl, (C₁-C₄)alkoxycarbonyl,halogenated ethoxycarbonyl, (C₃-C₅)alkenylcarbonyl andarylmethoxycarbonyl; and R′ is selected from the group consisting ofhydrogen, methyl, ethyl, propyl, isopropyl, (C₄-C₉)aliphatic alkyl,(C₃-C₉)alicyclic alkyl, aryl, heteroaryl, aryl(C₁-C₃)alkyl,heteroaryl(C₁-C₃)alkyl, (C₁-C₉)aliphatic alkyloxy, (C₃-C₉)alicyclicalkyloxy, aryloxy, heteroaryloxy, aryl(C₁-C₃)alkyloxy, heteroaryloxy,heteroaryl(C₁-C₃)alkyloxy, (C₁-C₉)aliphatic alkylthio, (C₃-C₉)alicyclicalkylthio, arylthio, heteroarylthio, aryl(C₁-C₃)alkylthio,heteroarylthio, and heteroaryl(C₁-C₃)alkylthio.
 6. The compound of claim5, wherein Y and E are independently selected from the group consistingof oxygen and sulphur.
 7. The compound of claim 5, wherein: E is oxygen;R′ is ethyl; and G is selected from the group consisting of hydrogen,trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, andt-butyldiphenylsilyl.
 8. The compound of claim 5, wherein: Y and E areoxygens R′ is ethyl; and G is hydrogen.
 9. The compound of claim 5,wherein: Y and E are oxygen; R₁, R₂, R₃ and R₄ are methyl; R′ is ethyl;and G is t-butyldimethylsilyl.
 10. A process for preparing the compoundof claim 1, the process comprising reacting a compound of formula (IV):

with up to one or less than one molar equivalent of an activatedderivative of formula (V):

in the presence of a first base, in at least one first aprotic inertsolvent, at temperatures between −80° C. and +50° C., to obtain anintermediate (IVbis):

and reacting the intermediate (IVbis) with a further equivalent of asecond base, in a second aprotic inert solvent, then adding at least onemolar equivalent of a 2-halopropionyl derivative of formula (VI):

at temperatures between −80° C. and +50° C., to form the heterocycliccompound of formula (I), wherein: Y is selected from the groupconsisting of oxygen, sulphur and NR₅; R₁, R₂, R₃ and R₄ areindependently selected from the group consisting of hydrogen, methyl,ethyl, (C₃-C₉)aliphatic alkyl, (C₃-C₉)alicyclic alkyl, heteroaryl,heteroaryl(C₁₋₃)alkyl, aryl, and aryl(C₁-C₃)alkyl, optionally mutuallycombined to form an o-phenylene structure with the 1,3 imidazolidinering, such as a benzo[d]-2,3-dihydro-1H-imidazole structure, and, suchthat when R₁ is coupled to R₂ and R₃ is coupled to R₄, they mutuallycombine to form an alkylene group or a cyclic spiro structure, such asligands of heterocyclo 1,3-imidazolidine; E is selected from the groupconsisting of oxygen and sulphur; R is selected from the groupconsisting of hydrogen, methyl, ethyl, propyl, isopropyl,(C₄-C₉)aliphatic alkyl, (C₃-C₉)alicyclic alkyl, and1-haloethyl(—CHX—CH₃) only when E is oxygen, aryl, heteroaryl,aryl(C₁-C₃)alkyl, heteroaryl(C₁-C₃)alkyl, (C₁-C₉)aliphatic alkyloxy,(C₃-C₉)alicyclic alkyloxy, aryloxy, heteroaryloxy, aryl(C₁-C₃)alkyloxy,heteroaryl(C₁-C₃)alkyloxy, (C₁-C₉)aliphatic alkylthio, (C₃-C₉)alicyclicalkylthio, arylthio, heteroarylthio, aryl(C₁-C₃)alkylthio, andheteroaryl(C₁-C₃)alkylthio; Y₁ is a nucleofugal group; the first andsecond base are independently selected from the group consisting of analkali metal hydride, a (C₁-C₄)alkyllithium derivative, an aryllithiumderivative, a heteroaryllithium derivative and an alkali metal; X is ahalogen selected from the group consisting of chlorine, bromine andiodine; and Y₂ is a nucleofugal group.
 11. The process of claim 10,wherein: the activated derivative of formula (V) is the 2-halopropionylderivative of formula (VI); and the process forms at least oneheterocyclic compound selected from the group consisting of forpreparing the compounds (Ic), (Id), (Ie), and (If):


12. The process of claim 11, wherein: the activated derivative offormula (V) and the 2-halopropionyl derivative of formula (VI) are bothracemic or optically pure but mutual enantiomers; and the processfurther comprises separating product stereoisomers by chromatography toobtain the heterocyclic compound as a racemate or a pure stereoisomer.13. A process for inverting the configuration of the stereocentresbinding the substituent X in the compounds (Ic), (Id), (Ie) and (If) ofclaim 4, the process comprising catalyzed acid rebalancing followed bychromatographic separation to isolate resulting diastereoisomericproducts.
 14. The process of claim 13 wherein: R₁, R₂, R₃ and R₄ of thecompounds (Ic), (Id), (Ie) and (If) represent identical substituents;and the mesoforms (Id) and (If) are transformed into a correspondingracemate (Ic)+(Ie).
 15. A process for preparing the compound of claim 5,the process comprising reacting a compound of formula (I):

under Reformatsky conditions, in the presence of a reducing agent, witha compound of formula (III):

at temperatures between −50° C. and +150° C., to form the compound offormula (IIIb), wherein: X is a halogen selected from the groupconsisting of chlorine, bromine and iodine; Y is selected from the groupconsisting of oxygen, sulphur and NR₅; R₅ is (C₁-C₉)aliphatic,(C₃-C₉)alicyclic, (C₃-C₉)heterocyclic, phenyl, aryl, or heteroarylcarrying up to three substituents selected from the group consisting ofhalogen, nitro group, and (C₁-C₃)alkoxy; E is selected from the groupconsisting of oxygen and sulphur; R is selected from the groupconsisting of hydrogen, methyl, ethyl, propyl, isopropyl,(C₄-C₉)aliphatic alkyl, (C₃-C₉)alicyclic alkyl, and1-haloethyl(—CHX—CH₃) only when E is oxygen, aryl, heteroaryl,aryl(C₁-C₃)alkyl, heteroaryl(C₁-C₃)alkyl, (C₁-C₉)aliphatic alkyloxy,(C₃-C₉)alicyclic alkyloxy, aryloxy, heteroaryloxy, aryl(C₁-C₃)alkyloxy,heteroaryl(C₁-C₃)alkyloxy, (C₁-C₉)aliphatic alkylthio, (C₃-C₉)alicyclic,alkylthio, arylthio, heteroarylthio, aryl(C₁-C₃)alkylthio, andheteroaryl(C₁-C₃)alkylthio; R₁, R₂, R₃ and R₄ are independently selectedfrom the group consisting of hydrogen, methyl, ethyl, (C₃-C₉)aliphaticalkyl, (C₃-C₉)alicyclic alkyl, heteroaryl, heteroaryl(C₁-C₃)alkyl, aryl,and aryl(C₁-C₃)alkyl, optionally mutually combined to form ano-phenylene structure with the 1,3 imidazolidine ring, such as abenzo[d]-2,3-dihydro-1H-imidazole structure, and, such that when R₁ iscoupled to R₂ and R₃ is coupled to R₄, they mutually combine to form analkylene group or a cyclic spiro structure, such as ligands ofheterocyclo 1,3-imidazolidine; G is selected from the group consistingof hydrogen, (C₁-C₄)alkyl, methoxymethyl, methylthiomethyl, allyl,propargyl, methoxyethoxymethyl, (C₁-C₉)dialkylboryl,9-borabicyclonon-9-yl, 2,2,2-trichloroethoxymethyl, tetrahydropyranyl, asubstituted ethyl group selected from the group consisting of1-ethoxyethyl, 1-methyl-1-methoxyethyl, and trichloroethyl, anaryl-substituted methyl group selected from the group consisting ofphenylmethyl, diphenylmethyl, triphenylmethyl, p-methoxyphenylmethyl,o-nitrophenylmethyl, p-nitrophenylmethyl, and p-chlorophenylmethyl, asubstituted silyl group selected from the group consisting oftrimethylsilyl, triethylsilyl, t-butyldimethylsilyl, andt-butyldiphenylsilyl group, formyl, (C₁-C₅)alkanoyl, halogenated(C₁-C₃)alkanoyl, an aryloyl selected from the group consisting ofbenzoyl, p-methylbenzoyl, and naphthoyl, (C₁-C₄)alkoxycarbonyl,halogenated ethoxycarbonyl, (C₃-C₅)alkenylcarbonyl andarylmethoxycarbonyl; and L is a nucleofugal ligand selected from thegroup consisting of halogen, formyloyloxy, acetoxy,(C₂-C₅)alkylcarbonyloxy, (C₃-C₉)cycloalkylcarbonyloxy, a (C₁-C₅)acyloxythat is unsaturated or halogenated at a position vicinal to thecarbonyl, arylcarbonyloxy, (C₁-C₇)alkylsulphonyloxy, arylsulphonyloxy,(C₁-C₇)alkylsulphonyl, arylsulphonyl, (C₁-C₇)alkylsulphinyl, andarylsulphinyl, C₇)alkylsulphenyl and arylsulphenyl, with the provisosthat: 1 to 5 molar equivalents of powdered zinc is present with respectto the compound of formula (III); and 0.5 to 3 molar equivalents of thecompound of formula (I) is present with respect to the compound offormula (III).
 16. A process for preparing an intermediate of formula(IIIe):

the process comprising reacting the compound of claim 5 with analcoholate for about 1 hour at a temperature between −20° C. and +50° C.to form the intermediate of formula (Me), wherein: G is selected fromthe group consisting of hydrogen, (C₁-C₄)alkyl, methoxymethyl,methylthiomethyl, allyl, propargyl, methoxyethoxymethyl,(C₁-C₉)dialkylboryl, 9-borabicyclonon-9-yl, 2,2,2-trichloroethoxymethyl,tetrahydropyranyl, a substituted ethyl group selected from the groupconsisting of 1-ethoxyethyl, 1-methyl-1-methoxyethyl, andtrichloroethyl, an aryl-substituted methyl group selected from the groupconsisting of phenylmethyl, diphenylmethyl, triphenylmethyl,p-methoxyphenylmethyl, o-nitrophenylmethyl, p-nitrophenylmethyl, andp-chlorophenylmethyl, a substituted silyl group selected from the groupconsisting of trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, andt-butyldiphenylsilyl group, formyl, (C₁-C₅)alkanoyl, halogenated(C₁-C₃)alkanoyl, an aryloyl selected from the group consisting ofbenzoyl, p-methylbenzoyl, and naphthoyl, (C₁-C₄)alkoxycarbonyl,halogenated ethoxycarbonyl, (C₃-C₅)alkenylcarbonyl andarylmethoxycarbonyl; and E₁ is selected from the group consisting of(C₁-C₄)alkyl, allyl, arylmethyl, diarylmethyl, and triarylmethyl; andthe alcoholate is selected from the group consisting of (C₁-C₄)aliphaticalcoholate, arylmethoxylate, diarylmethoxylate, and triarylmethoxylateof an alkali metal.
 17. A process for preparing a compounds of formula(II);

the process comprising reacting the compound of claim 5 with 1 to 20molar equivalents of hydrogen peroxide in the presence of from 1 to 10molar equivalents of an alkali metal hydroxide, with respect an amountof the compound of claim 5, in an aqueous organic solvent, at atemperature between −10° C. and +30° C. and, after the reacting, addinga reducing agent, to form the compound of formula (II), wherein: G isselected from the group consisting of hydrogen, (C₁-C₄)alkyl,methoxymethyl, methylthiomethyl, allyl, propargyl, methoxyethoxymethyl,(C₁-C₉)dialkylboryl, 9-borabicyclonon-9-yl, 2,2,2-trichloroethoxymethyl,tetrahydropyranyl, a substituted ethyl group selected from the groupconsisting of 1-ethoxyethyl, 1-methyl-1-methoxyethyl, andtrichloroethyl, an aryl-substituted methyl group selected from the groupconsisting of phenylmethyl, diphenylmethyl, triphenylmethyl,p-methoxyphenylmethyl, o-nitrophenylmethyl, p-nitrophenylmethyl, andp-chlorophenylmethyl, a substituted silyl group selected from the groupconsisting of trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, andt-butyldiphenylsilyl group, formyl, (C₁-C₅)alkanoyl, halogenated(C₁-C₃)alkanoyl, an aryloyl selected from the group consisting ofbenzoyl, p-methylbenzoyl, and naphthoyl, (C₁-C₄)alkoxycarbonyl,halogenated ethoxycarbonyl, (C₃-C₅)alkenylcarbonyl andarylmethoxycarbonyl; and the aqueous organic solvent is selected fromthe group consisting of dioxane, tetrahydrofuran, N,N-dimethylformamide,(C₁-C₄)aliphatic alcohol, N,N-dimethylacetamide and N-methylpyrrolidone.18. The process of claim 10, wherein the first and second aprotic inertsolvent are independently selected from the group consisting oftetrahydrofuran, dioxane, 1,2-dimethoxyethane, a C₆ alicyclichydrocarbon, a (C₆-C₁₀)aliphatic hydrocarbon, a benzene, an(C₁-C₃)alkylsubstituted benzene, a (C₁-C₃)dialkylsubstituted benzene, a(C₁-C₃) trialkylsubstituted benzene, a halogenated (C₁-C₃)aliphatichydrocarbon, glyme, diglyme, a di(C₁-C₄)alkylether,N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone andhexamethylphosphoramide.